P1231: IMPACT OF ARID1A AND TP53 MUTATIONS IN PEDIATRIC REFRACTORY OR RELAPSED MATURE B-CELL LYMPHOMA TREATED WITH CAR-T CELL THERAPY
Authors: Qinlong Zheng, Yang LI, Yang Liu, Keyan Yang, Ling Jin, Jing Yang, Shuang Huang, Ying Liu, Rong Liu, Wei Liu, Ansheng Liu, Yonghong Zhang
Journal: HemaSphere (2023)

Topic: 20. Lymphoma Biology & Translational Research Background: The outcome of pediatric patients with refractory or relapsed mature B-cell lymphoma (r/r MB-NHL) is very poor, and a chimeric antigen receptor T-cell therapy (CAR-T), has been used for treating these patients with significant improved clinical outcome, but there are still a proportion of patients display no response and relapsed after CAR-T cell treatment. Proposed factors contributing to CAR-T failure include T cell deficiencies, immunosuppressive tumor microenvironment, and tumor-intrinsic genomic alterations that are detrimental to response outcomes. Aims: The purpose of this study was to investigate whether the tumor-intrinsic somatic genetic alterations have impact on the outcomes of CAR-T treatment in a Chinese cohort of 89 pediatric patients with MB-NHL and to analyze the associations between genetic features and treatment outcomes. Methods: 89 pediatric patients treated at multiple clinical centers of the China Network of Childhood Lymphoma (CNCL) from February 2019 to September 2021 were included in this study. The targeted next-generation sequencing (tNGS) of a panel of lymphoma-associated genes were performed on initial diagnostic tumor samples in patients. Survival rates and relapse by genetic features and clinical factors were analyzed. Survival curves were calculated using a Log-rank (Mantel-Cox) test. Wilcox sum-rank test and Fisher’s exact test were applied to test for group differences. Results: A total of 89 driver genes with somatic mutations were identified. The most frequent mutated genes were TP53 (66%), ID3 (55%), ARID1A (31%), CCND3 (29%), and DDX3X (26%)(Figure 1a). The incidence of ARID1A mutation and co-mutation of TP53 and ARID1A in patients with r/r MB-NHL was significantly higher than that in patients with initial remission (p = 0.006; p = 0.018 respectively). Further analysis of variant allele frequency (VAF) showed a significant higher percentage of VAF of ARID1A and TP53 mutations in patients with r/r MB-NHLs as compared with that in patients with initial remission (p = 0.0075; p = 0.0025 respectively). CAR-T cell treatment significantly improved the survival in r/r MB-NHL patients (received CAR-T therapy mOS = 12.6 months, log-rank p = 0.00081) (Figure 1b), but patients with ARID1A or ARID1A and TP53 co-mutation had poor survival after CAR-T cell treatment when compared to the patients without such mutations (ARID1A-mut mOS = 3.85 months, log-rank p = 0.0095; ARID1A and TP53 co-mutation mOS = 2.37 months, log-rank p = 0.014) (Figure 1c and 1d). Conclusion: This study demonstrates children with MB-NHL harbouring ARID1A or TP53 and ARID1A co-mutation were insensitive to initial conventional chemotherapy and subsequent CAR-T treatment, and associated with disease progression or relapse. Examination of ARID1A and TP53 mutaion status at baseline might had a prognostic value and risk-adapted or more effective therapies shuould be considered for the patients with these high-risk genetic alterations.Keywords: CAR-T, B cell lymphoma, Pediatric, Somatic mutation